No. 3561.

NOVEMBER 28, 1891.THE LANCET,

The Croonian LecturesON THE

PROGRESS OF DISCOVERY RELATING TOTHE ORIGIN AND NATURE OF

INFECTIOUS DISEASES.Delivered at the Royal College of Physicians, London,

BY J. BURDON-SANDERSON, M.D. ED., F.R.S., &c.,PROFESSOR OF PHYSIOLOGY IN THE UNIVERSITY OF OXFORD.

LECTURE IV.

I PROPOSE to bring these lectures to a close by a study- of the subject of "Specificity"—a word which we applyto diseases just as we do to plants and animals. Theame of a disease stands for the ensemble of the patho.logical phenomena which present themselves togetheror in succession in a case of that disease, or in the

(body after death; and the conception which we maythus form of it may be more or less complete even in’the absence of any certain knowledge as to its nature orcause.

It may be stated generally that a specific disease hasmore individuality, more unity, than any other. The

,question we have now to consider is whether this specificitycan be explained by referring it to the external causes bythe operation of which we believe the disease to be pro-.duced. If we can so explain it, we bring the disease itself

within re&ch of experimental investigation. From themoment that a disease can be regarded as not merely a com-

plex of symptoms and lesions, but as the operation of aknown cause, which can be defined by the physicist, thechemist, or the biologist, its phenomena become parts of a,physiological process to be investigated, whether in theward or in the laboratory, by physiological methods. I,propose to-day, after a very brief preliminary discussion ofthe relation between the specific character of infective- filiseases and their external causes, to bring under your,notice a series of examples of such diseases, in the

1J.ope that I may be able to show that, however in-adequate our knowledge may be as yet, there is reasonto anticipate that at no very distant period it may bepossible to regard all acute diseases as physiological pro-.ceeses.

_ _ - .. -- - . - -- -- . -PART 1. The Origin, of Bacteriology -May I begin by re-ferring to a paper written by me in 1869 " On the IntimatePathology of Contagion,"1 in which the etiology of the acuteinfective diseases was discussed, with such light as we then,possessed? At that time the ideas of pathologists as to theorigin of infective diseases were vague. Contagia were re-garded as vaporous or gaseous, and " sewer gas " in particu-lar was thought to be capable of producing any of the’zymotic diseases. But the laborious investigations of"Chauveau had begun the new era by proving, as regards aseries of communicable diseases in animals, that the- Mtar Mt6i"6t—the substance which, when introduced intothe body of a susceptible animal, givfsriseto the process bywhich it was itself produced-is neither soluble nor diffu-sible, but consists of particles of indefinite minuteness’separable by subsidence or filtration from the liquid inwhich they are suspended.In the year I have mentioned, 1869, I spent some time at

Lyons, and had the opportunity of witnessing and takingpart in M. Chauveau’s experiments. Subsequently Imade a series of experiments on vaccine, the purpose ofwhich was not to show that the "infective particles" in’question were living organisms, but to prove that in thiscase, as in the others, the activity of the lymph is due totheir presence ; but in discussing these results I drew theinference from them that these particles are " probablyorganised beings," and that their powers of producing dis-ease are due to their "organic development." The groundfor this inference was that i6 afforded a satisfactoryexplanation of the two "facts" which at that time ap-

1 On the Intimate Pathology of Contagion. (Twelfth Report of theMedical Officer of the Privy Council, p. 229.)

peared among the most important as well as the best

ascertained in relation to the subject. These were, as statedin the paper I have referred to, (1) that 11 in the body of theinfected individual the particles of contagium rapidly re-produce themselves," and (2) that "out of the body they arecapable of resisting for very long periods the influencfs ofconditions which, if not restrained bv organic action, wouldproduce chemical decomposition." During the years whichfollowed, very little progress was made in elucidating therelation between specific diseases and their causes ; foralthough this period was rendered for ever memorable inthe history of the healing art by the triumph of Listeriansurgery all over the world, and a vast store of knowledgewas acquired and accumulated as to the etiology of trau.matic diseases, and as to their dependence on externalcontamination, no precise knowledge of specific microphyteswas acquired until, in 1876, Dr. Koch made his first greatdiscovery of the mode of growing the bacillus anthracisoutside of the living body, and of its remarkable life-history—a discovery which, as regards anthrax, appeared toafford a complete explanation of both of the facts which Ihad emphasised in 1869 : the rapid growth of the bacillusinside, its resistance outside of the infected organism. Atfirst this great and fundamental discovery was not o pro-ductive as might have been expected, for for several yearsthe bacillus anthracis was almost the only specific diseaseproducing microphyte which could be so cultivated in apure state. Probably the most important direct advantagewhich arose from it was that it brought the discoverer tothe front, and led to his abandoning the practical duties ofhis profession, in order to devote himsetf to those patho-logical investigations to which almost all the new know-ledge which I have endeavoured to embody in these lecturesis directly or indirectly due. The reason why progresswas not more rapid was that at that time no generalmethod existed for the discrimination of the species of

. "I J , J 1 i. - . pit- _ ,

micropnyues oy line cieierminarioii or tjneu morpno-logical and physiological characters. It was recognisedby all who were concerned in what are now calledbacteriologicalinvestigations-the word "bacteriology hadnot then come into use-that the question of the hourwas to find out how to sort pathogenic from harm-less species and from each other. Many were theefforts to solve thi problem, some of which were partiallysuccessful. In looking back at that time one wondershow it was that it occurred to no one how to makethe egg stand up as it ought ti do. But it was not

until 1880, as you all know, that Dr. Koch, by his methodof cultivation on the surface of solid media, at once andfor ever swept away difficulties which till then had beeninsuperable. As this method has rendered it possible tomake out the etiology of each of the specific diseases whichI shall have to discuss to-day, I may be permitted to occupya few moments in telling you how the discovery was arrivedat.3 It had been known to mycologists that when youexpose a freshly cut surface of a boiled potato to the air,and then keep it at a suitable temperature and protect itfrom evaporation as well as from further contamination fora few days, a number of points of growth appear on it,coloured or colourless. On investigating this phenomenon,Dr. Koch found that each point was a colony of micro-

phytes of one species which had ar’sen by the multipli.cation of a single individual at the spot at which it fell ;so that if several species were represented by colonies, thecolonies representing them were separated from each other.He further found that colonies of different species exhibit tothe lenq, or eB en to the naked eye, differences of form orarrangement which were often even more characteristicthan those observable microscopically. Had the same

atmosphere" germs " fallen into a nutritive liquid-e.g.,into a saucer of bouillon of the same size as the potato-they would have grown as well or better, but the growthswould have been inseparably mixed. Falling on a concretesurface, each germ vegetated after its kind, without mixingwith its neighbours. The potato experiment was the eggof Columbus. It not only suggested a method of sorting,but brought to light a new order of characteristic distinc-tions. No sooner had Dr. Koch recognised this than he setto work to substitute for the sliced potato a solid mediumwhich should have all the nutritive advantages of the liquid’media previously in use. This he accomplished by addit".2 Koch: Cohn’s Beitr. zur Biol. der Pflanzen, vol. ii., p. 277, 1876.3 Koch: Zur Untersuchung der Pathogenen Organismen. (Mittheil-

ungen an der k. Gesundheitsamte, vol. i.)Y

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to them gelatine or "agar" in sufficient quantity to makethem set at the required temperature, using gelatine whensummer temperature was suflicient, agar 4 for those micro-phytes which refused to grow at any temperature otherthan that of the body. One step more was wanted. Inorder to carry out the sorting process eflectually it wasnecessary to sow the microphytes, contained say, in thefraction of a drop of blood, over as large a surface as pos.sible. Obviously this must be done by dilution. Theplan adopted was to add the droplet to an ocean of thegelatinised medium, mix thoroughly, pour the mixture on ahorizontal glass plate, allow it to set, and let it standat the proper temperature. In this way the bacterial in-habitants of the droplet were distributed over an extremelywide surface, and consequently the colonies which resultedfrom their growth were relatively far apart from each other.All this was realised by Dr. Koch in all its technicaldetails with such completeness that, excepting for specialpurposes, it has scarcely been improved. Its value as ameans of investigation cannot be over-estimated. We havealready had occasion to see how it serves for the enumera-tion of the total number of microphytes which any liquidcontains ; but its chief use is that it enables the bacterio-logist to fish out particular species from the rest, in orderto test their pathogenic or other endowments. Into thetechnique of this fishing process I will of course not enter.The diseases which I propose to refer to as illustrationsof what has been done during the last ten years in deter-mining the nature of the relation between etiologicaland pathological specificity, between specificity of causeand specificity of process, are tuberculosis, typhoidfever, pneumonia, tetanus, and diphtheria. Of tuber-culosis I shall speak only with reference to its mode oforigin.

PART II. Etiology of Specific Infective Diseases.Tuberculosis.-Dr. Koch’s third discovery,5 that of the

bacillus tuberculosis, was a triumph of scientific insightand technical skill no less remarkable and no less fruitfulthan the second. When on March 24th, 1882, he madethe bold but perfectly justified statement that he haddiscovered not merely a constant concomitant of thetuberculous process, but its cause, and had thereby forthe first time given a complete proof of the parasiticnature of an infective disease of man, he did so on twogrounds-namely, (1) that in the examination of the mostvaried forms of tuberculous disease in man and animals,the presence of the bacillus could be demonstrated bycharacteristic microscopical characters, and (2) that it couldbe cultivated outside of the body without mixture withother microphytes, the pure culture so obtained beingendowed with the same power of communicating thedisease to animals that was possessed by the pathologicalproduct (diseased tissue or sputum) from which it wasderived. Both the methods by which these proofs wereobtained-the method for demonstrating the presence ofbacilli in tissues and sputum and the method of culti-vation-were exclusively due to Dr. Koch’s ingenuityand perseverance. I need not refer to his first methodof preparing and staining the bacillus of tubercle, forit has been replaced by better ones, which are now sowell established that they can be used clinically as a

means of diagnosis ; but it is still of interest to refer to themeans by which he overcame difficulties which then stoodin the way. Finding that the tubercle bacillus would notgrow in any of the media commonly used for cultivation,but that it would grow in serum at the temperature of thebody, he sought for and obtained a method of gelatinisingthis liquid so as to give it the advantages of a concretemedium. For a succession of years serum rendered gela-tinous by his method was the only soil on which the tuber-culous bacillus was grown’; but recently its manipulationhas been much facilitated by the discovery of Dr. Roux thatpeptone agar containing a certain percentage of glycerinecan be advantageously substituted for it.6 In this waytuberculosis (which on pathological grounds -had been re-garded as a kind of secondary or infective inflammationdistinguished from other secondary inflammations by its

4 Agar sets like gelatine, but remains solid at a higher tempera-ture.5 Koch: Die Aetiologie der Tuberculose. (Berliner k. Wochenschrift,

April 10th, 1882.)6 Nocard et Roux: Sur la Culture do Bacille de la Tuberculose.

(Annales de l’Institut Pasteur, vol. i., p. 19.)

relative chronicity and by its localisation in the lymphaticsystem) was proved to be etiologically among the mostspecific of infection processes, for in no instance can

the characters of the morbific agent be specified inmore precise terms. The anatomical knowledge whichwe possessed twenty years ago was sufficient to provethat, notwithstanding the endless variety of the ulteriormanifestations of tubercle, the origin and develop-ment of the tuberculous process differed from those-of any other human disease. But, as so often happensin physiology and pathology, this old knowledge hashad to give place so completely to that which has been,more newly acquired that, as regards the essential natureof the structural change which constitutes tubercle, italmost seems as if one might sweep away all that wasdone before 1880 and no one would be the worse for it.There could be no greater mistake. The reinvestiga-tion of the subject by better methods has not shown theold observations to be wrong, but only given them moreprecision and exactitude. To the observer of 1890, facts of’essential importance are known which in 1870 had not beenrevealed-viz., the nature of the agent, and the morpho-logical characteristics of its action. By using methods inwhich both of these elements are taken into account,Baumgarten, Cornil, and Yersin7 have been able to give us.a " revised version" of the origin and early developments ofthe tuberculous process, which, although perfectly consistentwith the old one, is stated in more precise language and ingreater detail. It has, I think, been shown that the.tubercle bacillus has no direct phlogogenic action-i.e.,that its primary action is to excite germinative changes.(proliferation) in tissue cells, particularly in those ofadenoid tissue, so that, in its origin, the process’ is in--dependent both of active congestion and of emigration of-leucocytes.Typhoid Fever.-The relations of typhoid fever to tuber-

culosis are sufficiently close to make it convenient to place.it first among the more acute infective diseases on our list.There is none of which the etiology has been more seriouslystudied, but also none as to which contradictory theories.have been advanced with more confidence. Even now ourknowledge on the subject is far from being so complete asone could wish. Here, as in the case of tuberculosis, it ison the mode of origin of the morbid process that we have to,fix our attention, and in this respect the two diseases to acertain extent resemble each other ; for one of the channels.by which the tuberculous infection enters the organism,,though by no means the one most frequently followed, is.the enteric lymphatic system. In typhoid fever it is pro-bably the only doorway. In typhoid fever, as in tuberculosis,the initial change seems to be proliferation of the folliculartissue of the intestinal mucous membrane and of themesenteric lymphatic glands; so that if we were to limitourselves to those forms of tuberculosis which are of entericorigin, the two diseases might be supposed to resemble oneanother. In reality the differences are more noteworthy than,the resemblances; for the typhoid process, if it begins likethe tuberculous, goes on very differently. It is much moreacute, and from the first shows itself to be much more

inflammatory than hyperplastic-by which I mean that the-affected parts are from the first the seat of active conges-tion and infiltration with leucocytes. Whether the typhoidprocess ever goes on to suppuration is matter of question,for certainly the lymphatic glands which are its principal,seat do not suppurate in the early stage of the disease, thoughin prolonged cases suppurations are among the most formid-able of its consequences. These no pathologist regards as.anything but secondary. They are infective inflammationsof typhoid fever, but not specifically so. They are due, not tospecific poison, but to the diminution of the alexeteriepower ofthe organism by which the common phlogogenic or pyogenicmicrophytes are able to get the upper hand. This is not afancy but a fact, for whenever in typhoid fever the tendencyto suppurate manifests itself, we find, as we should expecb,.that in the subcutaneous and submucous infiltrations whichoccur, the microphytes which are present have no specialrelations to typhoid fever, but are the clustercocci and chain-cocci which I discussed in my first lecture. The bearing ofall this on the question before us is this: that the cause oftyphoid fever must be sought for in the early stages of the

7 Baumgarten: Histogenese des Tuberkulosen Processes, Berlin,1885.Cornil: Les Bactéries, 3rd ed., Paris, 1890. Yersin: Etude sur leDéveloppement du Tubercule Experimental. (Ann. de l’Inst. Pasteur,vol. ii., p. 245.)

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disease and in the tissues primarily affected, particularly in theintestinal mucous membrane and lymphatic glands. The dis-covery of the typhoid fever" germ" was one of the earliest aimsof bacteriologists. One after another presented itself and hadto make way for a successor of equal but no better pretensions.fit was not until 1880 that Koch and Eberth8 simultaneouslylixed upon the micro-organism which has since borne Pro-fessor Eberth’s name, and has now become as familiar to thebacteriological student as the bacillus of anthrax or

tubercle. In form and even in mode of growth it is scarcelydistinguishable from the common saprophyte which we usedto call bacterium termo. It has active movements andlocomotive organs in the form of Hagelliform processes whichare thrown out from either side. These can be much betterseen photographically than by direct observation. By amethod of staining which I need not describe they havebeen specially studied by Dr. R. Pfeiffer,9 whose beautifulphotograph I now throw on the screen. Tne typhoid bacillusoccurs in the affected organs, and more especially in thespleen of patients, with great constancy, and can be trans-ferred with such certainty to external media that Dr.<Ga6ky was successful in 93 per cent. of the cases heexamined. Last lecture we saw on the screen the character-istic appearance which its colonies on gelatine platespresent. It grows luxuriantly in milk, and is one of thefew organisms which are capable of vegetating in drinking-water. In the organism it of course grows as an anserophyte,but it is equally or even more adapted to an serophyticexistence outside. Consequently, it must be regardedas much less specific than the bacillus of tubercle ; so that,on the supposition (the truth of which I do not mean’to assert) that both of them were in the distant,past derived from harmless ancestors, we should be ledto assign a much longer period of modification to thetubercle bacillus than to that of typhoid. Moreover, wecannot, as in the case of tubercle, assert that typhoid fever iscaused by the bacillus, for the experimental proof is want-ing. But even without that evidence, and with the know-ledge that in all probability typhoid fever will never be com-municated to animals, the constancy of the observed relation’between the occurrence and distribution of the bacillus, andthe existence and development of the disease seems to meand I believe all pathologists will agree with me) to leave- ao doubt whatever as to its etiological significance.Pneumonia, the next disease which I have on my list, is

one which, although not included by the Registrar-Generalamong those of zymotic origin, is, nevertheless, one con-cerning which preventive medicine is bound to occupy itself’very seriously. There is no acute disease which it is more.difficult to guard against, or which too often prematurely- cuts off valuable lives, than lobar pneumonia. That genuine.pneumonia is often a consequence of catching cold no onewill dispute. But I suppose that everyone in this room

would admit that when a person in good health is unex.pectedly attacked by this disease in consequence of a chill,there is something else which gives to the chill its formidablesignificance. Have we any idea what that something its ’,Several species of microphyte have during the last dozenyears been regarded as the cause of pneumonia. Early in 1883the late Dr. Friedltinder succeeded in cultivating from pneu-monic sputa a characteristic bacillus which was proved byinoculation to be pathogenic, but the satisfactory clinicaland experimental evidence was not more than sufficient tcentitle it to be regarded as one of the causes of pulmonaryinflammation. There is, however, another microphyteagainst which, as the corpus or corpusculum delicti, a greatdeal more may be said. This is known as the ’diplococcustpneumonise " of Weichselbaum or pneumococcus of Fraenkel.In English it may be called the pneumonia dumb-bell. It!history is as follows: In 1881 M. Pasteur observed, to hi!surprise, in inoculating a rabbit with the saliva of a chilcsnooted with hydrophobia, that the animal died rapidly osepticaemia. Subsequently Dr. Sternberg of Washington,lhaving observed that the inoculation of pneumonic sputucinduced in the rabbit symptoms similar to those observecby Pasteur,ll repeated the experiment with his own saliva,

8 Koch: Zur Untersuchung von Pathogenen Organismen. (Mittheil-ungen an der kaiserl Gesundheits-Aint, vol. i., 1881.) Eberth:Virchow’s Archiv, vols. lxxxi. and lxxxiii.

9 Frankel and Pfeiffer: Mikrophotographischer Atlas der Bakterien-kunde, plate liv. (Berlin, 1891.)

10 Sternberg: Der Mikrokok der Sputum-septik&aelig;mie. (Deutsche Med.Woch., 1887, p. 44.)

11 Pasteur: Note sur une Maladie nouvelle provoqu&eacute;e par laSalive &c. (Bulletins de l’Acad. de M&eacute;decine, 1881.)

As this animal also died of septicsemia, he was led to in-vestigate the subject bacteriologically, and found that inall the animals inoculated the same microzyme occurred,and that it corresponds with Pasteur’s description of themicrobe septicce7nique du salivc. Then, in 1886, the subjectwas cleared up by the investigation of Dr. A. Fraenkel, whoobtained pure cultures of Pasteur’s micrococcus in five outof seven cases of pneumonia that he examined, settled itsspecific characters and pathogenic action, and christened itpneumococcus. Daring the same year Dr. Weichsel-baum, working at Vienna, made an independent dis-covery of the same microphyte, and described it underthe name of "diplococcus." He investigated eighty-sixcases of pneumonia, and found it in eighty-one. Irre-spectively of its relation to pneumonia, which can nowscarcely be disputed, the pneumococcus is one of the mostremarkable microphytes known: first, because under cer-tain conditions it is so extremely virulent; but secondly,because it exemplifies the general principle that virulence isone of the most variable attributes of a microphyte-onewhich is most affected by its environment. Experimentsshow that even when introduced in the smallest quantityinto the subcutaneous tissue of a rabbit, it multiplies rapidlyboth in the blood and in the tissues, and that the septi-cfemia thus produced is of such rapid progress that, withthe exception of the enlargement of the spleen, it leaves nolesions behind it. On the other hand, it grows withgreat unwillingness outside of the body, even in mediawhich are especially suited to it, and, under the mostfavourable conditions, loses its toxicity in a few days. It isthus capable of thriving either as an aerophyte or as ananserophyte. As an serophyte it is inactive, but at onceregains its morbific power by transplantation from themedium in which it grows best to the living organism of arabbit. Like some human beings, it is active only in con-troversy ; its virulence declines from the moment that it isno longer required to struggle for existence. And now wemust endeavour to come to a conclusion as to the part whichthis very variable microphyte takes in human pathogeny,and for this purpose I wish to bring under your notice somefacts observed by my friend Dr. Netter, the accomplishedDirector of the Hygiene Laboratory of the Faculty ofMedicine in Paris, who, with the best possible clinicalOppurtinities, 11l1< Mie labour V1 years Lu this

ject, with special reference (1) to the constant presence ofthe pneumococcus in cases of croupous pneumonia ; (2) toits participation in other acute processes ; and (3) to theetiological significance of its presence in the saliva of appa-rently healthy persons. Having, to begin with, succeededin cultivating the microphyte in the first twenty-seven casesthat were admitted into hospital, without a single failure,he regarded the firms point as provisionally settled. As re-gards the second point, he found that in infective-i. e., secon-dary-inflammations of other internal organs the pneumo-coccus occurs with a frequency which is comparable withthat of streptococcus. Lastly, its presence in the saliva isheld by Dr. Netter to be a remainder of pneumonia.Finding that in ordinary individuals the saliva is free frompneumococcus, whereas it is usually to be met with in that ofpersons who have had pneumonia, he connects its presencewith the liability to recurrence of the disease which isoften observed. Time only can determine the value of thefacts on which this inference is founded. In any case thecausal relation which they suggest is a complicated one.For if the pneumococcus is in some apparently healthypersons always present, it seems evident that it cannot actalone. The sword of Damocles may be always there, butthe moment at which it falls must be determined by otherconcomitant causes-a catarrh, a disorder of the circulation,or possibly the operation of some more subtle infection,such as that of influenza. Still less can it be stated thatcroupous pneumonia is the only pathological outcome ofthe pneumococcus. In addition to the observations ofDr. Netter, to which I have already referred, we haveevidence of the most trustworthy kind as to its associationwith that most specific and infective of acute inflammations,epidemic cerebro-spinal meningitis-a disease which is oftenassociated with croupous pneumonia; and also a remarkableseries of cases of otitis of the middle ear published byZg,iifal.12 Its presence in the middle ear is of course easy to

12 Zaufal: Falle von gewisser acuter Mittislohrentzundung &c.(Several papers in Prager Med. Woch., 1889. Ref. in Baumgarten’sJahresb., 1889, p. 80.)

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understand, but how it finds its way into the cerebro-spinalcavity is difficult to explain.

Tetanus.-I wish now to ask your attention to twodiseases which, although they are not allied to each otherpathologically, have this in common-that in each a well-defined microphyte is forthcoming, and that each of theseacts rather by its chemical products than by itself, and, inparticular, that each exerts a special action on the nervoussystem. The history of the discovery of the tetanus bacillushas unusual interest. A dozen years ago traumatic tetanuswas not regarded as an infective disease. Dr. Heiberg ofChristiania had given good pathological grounds for

thinking that it was so, and several leading surgeons,particularly Sir Spencer Wells, had declared it to beso on clinical grounds. Soon afterwards experimentswere made on the subject both in France and Germany,but without result. It was not until 1884 that Carleand Rattone found that by inoculation of pus from a woundwhich had given rise to tetanus they could induce a similardisease in rabbits. A little later Nicolaier made theremarkable discovery that pure cultures of certain bacillicontained in garden soil produce tetanus when injectedsubcutaneously, in animals. Next year Rosenbach pro-duced tetanus in a number of animals by inoculatingmaterial from the seat of infection in a case of traumatictetanus under his care,13 and found Nicolaier’s garden-bacillus both in the original material and in the infectedanimals. The effect of the publication of Rosenbach’scommunication was immediate. On April 18th, 1886, thetetanus bacillus was demonstrated in Dr. Koch’s labora-tory. Then followed a series of clinical and experimentalinvestigations (in which, as usual, every country exceptingEngland took part), the result of which was that in avery short time the claim of the tetanus bacillus to beregarded ae the determining cause of the disease was estab-lished on the testimony of a suffident number of competentwitnesses. Biologically, the tetanus bacillus has two interest-ing pecularities. Its characteristic form, that of a drumstick,is connected with the fact that each rod is capable of pro-ducing a spore at its end, the width of which when matureexceeds considerably that of the rod itself. The obviouspresence of spores distinguishes it from most pathogenicmicrophytes, excepting of course the bacillus anthracis ;but the tetanus bacillus is still more remarkable as regardsits relation to oxygen. So far, we have found our morbificmicrobes to be, in the language of bacteriology, facultativeanaerophytes-i. e., capable of thriving either with or with-out access of air. The bacillus of tetanus is unconditionallyanaerobiotic. It was its extreme sensitiveness to oxygenthat made it in the first instance impossible to cultivate itotherwise than in an atmosphere of hydrogen. Sub.sequently the distinguished bacteriologist, Dr. Kitasato,found that, in common with other an&aelig;rophytes, the tetanusbacillus could be cultivated in tubes without exclusion ofoxygen, provided that a percentage of grape sugar wereadded to the gelatine. In this way the tetanus bacillus,which was at first a very difficult plant to grow, has becomefamiliar to bacteriological students from the very re-

markable characteristics which it presents in puncture-cultures.What) does this remarkable ainuropbyte do in the living

organism ? It might be expected that in an animal killed byit in the characteristic way that I have described, the bacilliwould be found everywhere. On the contrary, no lesion what-ever is to be found in any organ, and no trace of the microphyteitself, excepting in the immediate neighbourhood of the focusof infection. It is therefore obvious that the developmentof tetanus cannot be described as a contest, a struggle forexistence between the microphyte on one side ,and theorganism on the other; for here the tendency to multipli-cation, which we once considered as an essential in everyinfective process, is conspicuously absent. The bacillimultiply, but their multiplication is limited to the seat ofinfection, to the immediate neighbourhood of the wound.In the dissemination of the materies morbi they take nopart That is due to a poisonous product of their growth, inrespect of which the most remarkable fact that we know is

13 The case was one of frost-bite, in which tetanus had supervenedthree or four weeks after the exposure. The disease was communicatedin the first instance to a guinea pig by the subcutaneous insertion of afragment of dead skin Nicolaier: Beitr. zur Aetiologie des Wund-starrkrampfes. Inaug. Diss. Gottingen, 1885. Carle and RattoneStudio Sperimentale su’l’ Etiologia del Tetano. Giorn. del R. Accad. d.Med. di Torino, Marzo, 1884. Ref. from Baumgarten.)

that, although in a certain sense soluble, it spreads withextreme slowness through the organism.Diptheria-Although the etiology of diphtheria is a.

subject beset with diiliculties, recent researches, and parti.cularly the clinical and experimental investigations whichhave been lately made in Paris, both in the Pasteur In-stitute and in the hospitals, have, I think, dissipated a good’deal of the obscurity which existed a few years ago inrelation to it. In the early days of bacteriology, diphtheria.was one of the diseases which excited most interest fromthe circumstance that among the many microphytes whichfrequent the mucous surfaces which are its seat, the claim.of some one to be regarded as its cause could always beadvanced. The bacillus which is now admitted to bespecial to diphtheria was first recognised by ProfessorKlebs in 183 as constantly present in the superficial’layer of the membranous exudation, and in the courseof the following year it was successfully cultivated byDr. Loiner, of the Berlin Laboratory. It presents no.

very striking microscopical peculiarities, and is chieflydistinguished by the intense poisonous effects which itproduces in animals. Notwithstanding its characteristictoxical properties, its claim to be regarded as thefons 0&

origo mali was received with great hesitation, and chieflyfor three reasons-namely, first, that the symptoms whichit produces in rodents-sanguinolent infiltration of thecellular tissue at the seat of inoculation and of thelymphatic glands in relation with it, and sanguinolenteffusion into the serous cavities-are not those of diph-theria ; secondly, that cultivation of the diphtheria bacillus;.although derived from genuine cages of diphtheria, are notalways active ; and thirdly, that in man the microphyte is’anot met with in the blood or in any internal organ, but isconfined to the affected surface. For all these reasons itseemed difficult to determine whether the bacillus of L&ouml;fflermight not play the same part in diphtheria that the chain-coccus does in scarlatina, as an important accessory agent.in the production of the local lesions rather than as theinitiator of the disease. But, as I said before, the researchesof M. Roux, which were communicated two years ago tothe Royal Society in a Croonian Lecture, have done a gooddeal to alter the position of the subject. As regards allthe points investigated by LofHer in 1884, Roux confirmedthe accuracy of the work done by that most cautioUJobserver ; but he added to them two important dis-coveries-namely, first, that all the phenomena described byLoffier as produced by pure cultivation of the bacillusare also produced by the chemical products of its growth ;and secondly, that when dogs are used as test animals in-stead of rodents, the paralytic symptoms which above allothers are pathognomonic of diphtheria manifest them.selves in a characteristic way. At the same time (1889)that these researches were being carried on in Paris, Pro-fessor Brieger, in Berlin, included diphtheria in the general’investigation of bacterial poisons, of which he, in conjunctionwith Dr. C. Fraenkel,14 published the results in the springof 1890. Time will not permit me to give any account oi,this research. It is of more importance to note that theinvestigation has been continued from the chemical side, inthe Berlin Hygienic Institute during the present year’5 withvery great completeness. Confirming all the statements ofRoux as to the association of the toxical action with aproteid and as to the partial resemblance of the agent to anenzyme, they have, by a method similar to that employed*by Brieger the year before, finally obtained an albumose-i.e., a body presenting the characters of the transitional pro>teids which are formed in the process of peptonisation.,of such toxical activity that less than a milligramme of it.injected subcutaneously induces in the rabbit a fataldisease, with characteristic lesions of liver, kidneys, andother internal organs. Ib has, moreover, been shown thatthis substance, which is obtained from the culture ofL&ouml;ffer’s bacillus in the laboratory on a large scale, is also,elaborated in the bodies of the infected animals, andcan be obtained from them in a state of even

greater toxical activity than from the culture, thefatal dose being one-fifth of a milligramme;. with referenceto which fact it is important to notice that what youactually weigh is not the disease-producing zyme itself, buH

14 Brieger u. Fraenkel: Untersuchungen ueber Bacteriengifte(Berliner k. Wochenschrift, 1890, pp. 241 and 1133.)

is See Wassermann u. Proskauer, Deutche m. Woch., vol. xvii, p. 585.(April, 1891).

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merely the proteid b)dy, to which it is attached bybonds which are very easily broken. I need scarcely saythat it is this instability which constitutes the frightfuldifficulty of investigations of the kind we are now con-sidering.Let me now, in conclusion, bring before you the sum

of what we have learned from the examples we havehad before us-tuberculosis, typhoid fever, pneumonia,tetanus, and diphtheria. The question we have put before usin respect of each of the five diseases has been, How does thesupposed cause produce the effect attributed to it? Theanswers have been as different as the diseases. Somemorbific agents we have found to act mainly biotically-i.e., by virtue of their endowments as living organisms;others chiefly toxically-i.e., by virtue of the "toxines"which they produce. Thus in splenic fever, and in adifferent sense in tuberculosis, the morbific action is pre-eminently biotic; in diphtheria and tetanus preeminentlytoxic-i.e., the nexus between the morbific ager c and themorbid process is in the one case dissemination, in theother diffusion. In both cases a fatal influence spreads froma focus of infection, but in splenic fever the spread is by themultiplication and dispersion of myriads of bacilli, in theother by the slow contamination of the organism by apoisoc, which it is convenient to call provisionally toxin,though perhaps a proteid, and certainly pre-eminentlycolloidal. We might, therefore, classify infective diseasesin line, placing splenic fever at one end, tetanus at theopposite end, and the others in intermediate positions,according to the relative predominance of the toxic or bioticelement in the modus operandi of the microphytic agent.In such an arrangement we should have to bear in mindthat the two elements are not equally essential-that everymorbific microphyte acts primarily toxically-i.e , thatwithout toxical power no microphyte could live. Even inthe case of splenic fever, we have evidence that mitigatedbacilli do not multiply and are not disseminated in thebodies of susceptible animals-a fact which seems plainly toindicate that the reason why virulent bacilli do multiply isthat, by their direct action on the tissues, and by thus sur-rounding themselves with an environment in which theycan live, they acquire sufficient vigour to be aggressive.As regards the restriction of its power of multiplication anddissemination, the tetanus bacillus is comparable to themitigated anthrax bacillus, but with this important differ-ence-that it is able, without multiplication, to producepoison enough to destroy life.Another point relating to causal relation between micro-

phytes and the diseases they produce is that of the possiblesubstitution of one species for another. Our studies of to-day, especially if taken in connexion with what we havelearned in previous lectures as regards other microphytes,lead to the conclusion that in certain instances the samekind of infective action may be exercised, and consequentlythe same morbid process be initiated, by microphytes, of dif-ferent species-i.e., that in these cases, although the inter-vention of some microphyte is essential in order to bringthe morbific agent into existence, one may act as surrogateto another. In this respect I should be inclined to placetuberculosis, splenic fever, relapsing fever, and tetanus onone side of a line, and pneumonia, diphtheria, and scarlatinaon the other. Suppuration we know can be producedabiotically, and it has been shown that the most charac-teristic localised inflammations, those which exhibit mostof the specific character- such, for example, as cerebro-spinalmeningitis, median otitis, and osteo-myelitis-may each ofthem be generated by more than one species of microphyte.It seems probable that croupous pneumonia, when itassumes the epidemic character, may be occasioned by micro-

phytes other than the pneumococcus, and it has not vetbeen proved that even in diphtheria the bacillus of Lofflermav not be replaced by some other. ,

Time compels me to bring my unfinished task to a con.clusion. The lines of inquiry which I have endeavouredto follow in these lectures have been those along which Ibelieve that the advance of knowledge of the causationof acute diseases will, in the near future take place.I have endeavoured to show that, although the firstqualification of a disease-producing microphyte is thefaculty of living and multiplying in the living tissue, theresearches of recent years have taught us that its poison-ousness is even more essential than its adaptedness to aliving nutritive medium; so much so that the damagewhich it thereby inflicts on its living environment is a means

by which it modifies that environment for its own advantage.We have further seen that the contest which takes place inthe organism between invading microphytes and the livingelements of the invaded territory, is not a hand-to-hand fightbetween tissue elements and microphytes, but one in whichboth act, so to speak, at a certain distance, and that it is onein which the weapons are poisons and counter-poiaone, toxinesand anti-toxines, words which merely imply that the phy-siological endowments of these bodies are antagonistic.The question of infection, therefore, has become, as manyclear-sighted pathologists foresaw that it necessarily would,more and more chemical, less morphological. But in sayingthis we must carefully guard against its being implied thatany progress in the discovery of the chemical agencies bywhich diseases are produced and prevente:!, can be madewithout the bacteriological metnod, or that it is inthe least less necessary than before that all who in-tend to be pathologists should perfect themselves inthe technique which Dr. Koch created. If, there-fore, the questions which at this moment concern us

appear to be chiefly chemical, it means only that wehave got from the form to the substance, from the agent tothe action. Pathologists were never phytologists, and do notpretend now to be chemists. We care for microphytes notas botanical species, but as makers of toxines, and for toxinesnot as chemical compounds, but as producers of disease.For although, as not being organised, we must call themchemical, our chemical knowledge respecting them is so in-definite and inconsiderable that the chemist would scarcelyrecognise their existence. They possess certain nosogenicor alexeteric properties which appear to attach themselvesto proteids; but of their chemical nature the pathologist isable to say even less than the physiologist can of the so-called enzymes.

I must not end without saying a word as to the future ofpathology in this country, and particularly in this greatmetropolitan school of medicine. Unfortunately, it must beadmitted, whether we like it or not, that hitherto we havebeen too much contented to let other men labour, and com-placently to enter into their labours. I have in the courseof these lectures been disagreeably conscious-and it musthave been equally apparent to those who have listened tome-that the names I have had occasion to refer to as ofmen who have achieved the recent progress which it hasbeen my business to record, few-far too few-have beennames of our countrymen. Happily the promise of thefuture is more encouraging than the record of the past.We have now, if not a host, a considerable body of menwho know their business and how to do it-men youngenough not to have lost those exact habits of observationacquired by previous studies in physics and chemistry andin physiology, yet old enough to take a living interest inmedicine-men with a very definite understanding of whatpathology means and how it must be advanced-namely, bythat same method which Harvey commended to us so

emphatically over two hundred years ago: the searchingout of the secrets of nature by way of experiment. In thepart it has taken in the building and establishment of alaboratory for researches in pathology and pharmacologythis College has given substantial proof of its readiness tofollow Harvey’s counsel. It could not have raised a bettermonument to his memory. The success of the laboratoryis already assured. Small as it is, it has already become acentre of pathological work-a focus whence a salutaryinfluence in the direction of real progress is spreading inevery direction. Nor can it be doubted that when theadvance of the next ten years has to be chronicled, it will belooked back to as the beginning of a new era.

THE VACCINATION REPORT.-It is stated that theVaccination Commissioners will either take steps to issue aninterim report, or will so expedite their proceedings as tomake the comparatively early conclusion of their work aprobability.THE ALLEGED LEAD POISONING AT WAKEFIELD.-.

The Waterworks Committee of the Wakefield Corporationhave decided that Dr. Meymott Tidy and another expertshall be engaged to thoroughly investigate the question ofalleged lead-poisoning from the use of the water suppliedfrom the corporation works, with the object of ascertainingthe cause, and applying such remedial measuresas thecorporation may be advised to be necessary and expedient.